This proposal describes a series of fundamental and applied immunologic investigations focusing on the pathologic consequences of immunologic malfunction. This multidisciplinary research program includes studies of the etiologic agents, particularly viruses and autoantigens, which may initiate pathogenic immune responses resulting in disease. The mediators of immunologic injury which operate subsequent to the initiation of the pathologic immune response will be studied, particularly the complement system, its various constituents and the nature of their interactions which via the release of multiple enzymes mediate much immunologic injury and are capable of initiating blood coagulation and inducing systemic shock. Other mediators of immunologic injury which will also be studied include the neutrophilic and basophilic leukocytes, platelets, macrophages and the kinin system, all important in phlogogenic changes and hemostasis. The participation of lymphoid cells in immunologic responses and reactions, both as carriers of immunologic specificity and as effector cells in immunologic inflammation, will be studied. Finally, the nature of immunocompetent cells, i.e., B and T cells, in the detection of and response to antigens which eventuates in antibody formation or the development of sensitized cells on one hand, and immunologic tolerance on the other, will be investigated in depth in an attempt to gain knowledge which will provide a rational basis for the manipulation of the immune response.